INVITED REVIEW
Syncope, cerebral perfusion, and oxygenation

¹ Cardiovascular Research Institute Amsterdam and Departments of ² Medicine and ³ Physiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and ⁴ The Copenhagen Muscle Research Center and ⁵ Department of Anesthesia, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark

	ABSTRACT

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

During standing, both the position of the cerebral circulation and the reductions in mean arterial pressure (MAP) and cardiac output challenge cerebral autoregulatory (CA) mechanisms. Syncope is most often associated with the upright position and can be provoked by any condition that jeopardizes cerebral blood flow (CBF) and regional cerebral tissue oxygenation (cO₂Hb). Reflex (vasovagal) responses, cardiac arrhythmias, and autonomic failure are common causes. An important defense against a critical reduction in the central blood volume is that of muscle activity ("the muscle pump"), and if it is not applied even normal humans faint. Continuous tracking of CBF by transcranial Doppler-determined cerebral blood velocity (V_mean) and near-infrared spectroscopy-determined cO₂Hb contribute to understanding the cerebrovascular adjustments to postural stress; e.g., MAP does not necessarily reflect the cerebrovascular phenomena associated with (pre)syncope. CA may be interpreted as a frequency-dependent phenomenon with attenuated transfer of oscillations in MAP to V_mean at low frequencies. The clinical implication is that CA does not respond to rapid changes in MAP; e.g., there is a transient fall in V_mean on standing up and therefore a feeling of lightheadedness that even healthy humans sometimes experience. In subjects with recurrent vasovagal syncope, dynamic CA seems not different from that of healthy controls even during the last minutes before the syncope. Redistribution of cardiac output may affect cerebral perfusion by increased cerebral vascular resistance, supporting the view that cerebral perfusion depends on arterial inflow pressure provided that there is a sufficient cardiac output.

arrhythmia; blood pressure; cerebral blood flow; vasovagal; cardiac output

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

A SYNCOPE OR "COLLAPSE"¹ is a sudden loss of consciousness and postural tone. A syncope can be provoked by any condition that jeopardizes cerebral oxygenation. Most commonly a syncope is reflex mediated, also designated "neurally" or "vasovagal," and it typically develops in the upright position but may even occur in    the supine or seated positions, e.g., in the dental chair (14, 154, 176). There is a belief that the human cardiovascular system is exquisitely adapted for maintaining cerebral perfusion in the upright posture. Although the gravitational force creates pressure gradients in the circulation, humans can stand erect because gravitational pressures become partially neutralized by mechanisms that prevent lower extremity fluid accumulation (155). Nevertheless, ~1 million patients are evaluated for syncope annually in the United States, and ~1% of emergency department visits and hospital admissions are for evaluation of a syncope. Thus syncope has considerable medical, social, and economic impact: it is common, disabling, and possibly associated with a risk of sudden death (78), yet it is difficult to diagnose (37, 159). Conditions like a reduced central blood volume by bleeding or pooling, anxiety, pain, and also a variety of drugs that affect mean arterial pressure (MAP) and cardiac output (CO) render cerebral blood flow (CBF) inadequate for maintaining consciousness (14, 159, 176).

A perspective on syncope is presented with focus on the adjustment of the cerebral circulation to the upright position. The clinical implications of a syncope and potential countermeasures are discussed with emphasis on the critical dependency of the brain on the distribution of CO and regulation of CBF. Common conditions that jeopardize CBF are highlighted with respect to the major physiological events that are elicited with self-induced syncope, the postural reduction in MAP and CO, and the effects of hypocapnia and straining.

	SEQUENCE OF CLINICAL EVENTS

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

Documented records of the hemodynamic and clinical events that precede a syncope in daily life are difficult to obtain. Consequently, under laboratory conditions voluntarily induced syncopal episodes have been applied to document these events by use of two main approaches. Syncope may be almost instantaneously induced by the combination of hyperventilation and straining (33, 64). The circulatory response is different from that commonly observed after a vasovagal faint in which blood pressure does not overshoot after the event (186). In the "fainting lark" (see below), the reflex vasoconstrictor mechanism is functioning as opposed to the vasomotor failure of the vasovagal syncope. A similar overshoot in blood pressure and mean CBF velocity (V_mean) is observed also after a Valsalva maneuver (29, 130, 165). During more gradually induced arterial hypotension, the sequence of events can be studied by inducing vasovagal reactions in volunteers and patients with the use of vasodilating agents, standing and passive head-up tilt (HUT), subatmospheric pressure to the lower part of the body (LBNP), bleeding and/or venous occluding tourniquets, threat of instrumentation or venipuncture, and promoting mental stress (45, 136, 176). Also, observations in patients with cardiac syncope and with autonomic failure have contributed to the understanding of the events that are of importance for developing (pre)syncopal symptoms.

The fainting lark: voluntary self-induced instantaneous syncope. The fainting lark is a maneuver that combines effects of acute arterial hypotension by gravity and raised intrathoracic pressure with cerebral vasoconstriction in response to hypocapnia (64, 81). The maneuver induces almost instantaneous syncope in volunteers (95). The fainting lark has been used by children, high school students, and recruits as entertainment and also in the laboratory for research (64, 81, 95). Squatting in a full knee bend is combined with hyperventilation. The subject then suddenly stands up and performs forced expiration against a closed glottis. The maneuver provokes a precipitous and deep fall in arterial pressure, hyperventilation further reduces CBF, and the subject loses consciousness (Fig. 1; Ref. 185).

View larger version (52K): [in this window] [in a new window]   Fig. 1.   Cerebral blood flow velocity during self-induced syncope ("fainting lark"). At standing up, diastolic cerebral artery blood velocity suddenly drops to zero, finger plethysmogram disappears, and the subject instantaneously collapses with abrupt loss of consciousness and rapid restoration of cerebral artery blood velocity in the supine position. ETCO2, end-tidal carbon dioxide concentration. [From Ref. 185, with permission.]

Lempert and co-workers (94-96) applied the fainting lark in 59 students aged 20-39 yr who volunteered for self-induction of a syncope. A syncope was induced in 42 of 59 subjects. Prodromal symptoms were short lasting (<5 s), which is not surprising given the combined fall in arterial pressure and CBF. The loss of consciousness lasted 5-22 s. Myoclonal jerks lasting 1-16 s were observed in almost all of the 42 syncopal episodes after falling down. During the syncopal attack, the EEG, as in previous studies, showed a progressive slowing in the delta range and initial increase followed by a sudden reduction of brain-wave amplitude. This was in turn followed by a flattening of the trace ("flat" EEG) and then abrupt return of high-voltage slow activity before the normal background activity was restored. Myoclonic jerks occurring while the EEG is slow and "flat" are apparently of subcortical origin and are postulated to originate from abnormal firing of the reticular formation in the lower brain stem (95).

Vasovagal syncope. Prodromal symptoms and signs are usually reported by individuals experiencing a spontaneous vasovagal syncope in daily life. Prodromal signs are also observed when a vasovagal syncope is induced under laboratory conditions. The falls in MAP and cerebral perfusion pressure (CPP) are progressive, yet they are usually more gradual in a developing vasovagal syncope than those experienced with the deliberately induced hypotension. However, in one of three individuals with a vasovagal syncope, the collapse is reported to happen instantaneously and thus without warning (43, 159). Prodromal symptoms may start to appear minutes before the actual faint, but a period of only 5 s is not unusual (19). The patient feels uncomfortable in an ill-defined way. This may be manifested by symptoms of epigastric discomfort and vague nausea, sweating, and a desire to sit down or to leave the room. The pathophysiology of at least some of these symptoms is unclear, although there may be a role for pancreatic polypeptide, which is increased in near-fainting subjects (141). A general vagal discharge causing not only bradycardia but also release of pancreatic polypeptide is thought to be involved, inducing reflex relaxation of the stomach (140, 149).

If early warning symptoms of a syncope are ignored, the mild disturbance intensifies and symptoms like lightheadedness, fatigue, blurred and fading vision, palpitations, and tingling of the ears develop (19, 43, 160). The visual prodromal sensations are by a reduction in blood supply to the retina through the ophthalmic arteries. Because the eye, unlike the brain and brain stem, is not protected by the pressure-equalizing effects provided by the cerebrospinal fluid (CSF) and also because the retina is exposed to the intraocular pressure, collapse of retinal perfusion becomes manifest before the loss of consciousness. This relationship is studied by exposure of subjects to high G forces in whole body centrifuges. Sensations begin with diminution of vision, "gray out" (loss of color vision) that may progress to "blackout." A blackout takes place when the ischemic retina essentially ceases to function (183). Signs of an impending vasovagal faint are facial pallor, sweating, restlessness, yawning, sighing and hyperventilation, and pupillary dilatation (129, 160). The prodromal phase is most often associated with a relatively rapid heart rate (HR). With continuing hypotension, the individual has difficulty in concentrating, becomes unaware of his or her surroundings, and then loses consciousness and falls. Bradycardia occurs just before the actual faint. The final phase of a vasovagal attack is a rapid loss of consciousness with loss of postural tone. During the faint, the clinical picture resembles that of voluntarily induced syncope by the fainting lark. Myoclonic jerks however, appear to be less common in a spontaneous vasovagal syncope than in voluntarily induced syncope using the fainting lark (43). The duration of unconsciousness is usually brief, lasting less than 5 min. Of additional importance in the clinical picture of vasovagal syncope are the postsyncopal findings, characterized by profound fatigue, a persistence of pallor, nausea, weakness, sweating and oliguria, and a tendency toward recurrence of the reaction if the individual is returned to upright (43, 160).

Cardiac syncope. Syncope associated with a heart block or with cardiac arrhythmias is characterized by the suddenness of its onset and the lack of warning symptoms of cerebral hypoxia and autonomic discharge (19). The syncopal episode may develop in both the erect and the supine position. The patient is pulseless, and loss of consciousness ensues within 10 s and more rapidly when the individual is standing than in recumbency (179). Prolonged asystole provokes myoclonic jerks and incontinence of urine. Recovery is rapid with a sudden return of the pulse, flushing of the face, and usually full orientation of the patient. The flush occurs during an overshoot in arterial pressure. After the syncopal episode, the subject can be mobilized almost immediately. During asystole and vasodepression, cerebral hypoperfusion in the carotid sinus syndrome is normally compensated for by cerebral autoregulation (CA; Ref. 93).

Syncope due to orthostatic hypotension in patients with autonomic failure. Symptomatic orthostatic hypotension is the main problem in patients with autonomic failure with characteristic features related to the persistent decrease in MAP. Symptoms include lightheadedness and blurring of vision. A neck ache radiating to the occipital region of the skull and to the shoulders ("coat hanger" distribution) often precedes the loss of consciousness (11). The postulated mechanism of this virtually unique symptom of postural hypotension is ischemia in continuously contracting postural muscles. Other symptoms suggesting impaired muscle perfusion are lower back and buttock ache or angina pectoris. Typically, symptoms develop within minutes on standing or walking and resolve on lying down (11). The symptoms can be considered as prodromal and patients with autonomic failure quickly learn to use them as a warning signal so that they lie down to restore cerebral perfusion. If the patient remains upright, consciousness gradually fades and the patient falls slowly to his or her knees. Sudden postural attacks may, however, also occur. Symptoms and signs of autonomic activation like sweating or a vagally induced bradycardia are absent in patients with autonomic failure.

In the following sections the cardio- and cerebrovascular events that usually take place in the transition to the upright position are discussed. First, the methods used to gauge the cerebral circulation in humans are addressed.

	CEREBRAL BLOOD FLOW AND OXYGENATION

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

In humans, steady-state values of cerebral perfusion are reported as the clearance of gases including N₂O and ¹³³Xe, of a tracer such as indocyanine green, or as the arterial-jugular venous O₂ difference under conditions of assumed stable rate of brain metabolism. Transcranial Doppler (TCD)-determined V_mean of large cerebral arteries has a favorable temporal resolution compared with the more traditional techniques for assessing CBF. Changes in the local cerebral oxygenation are reflected by functional magnetic resonance and, more dynamically, by dual-wavelength near-infrared light spectroscopy (NIRS; Refs. 9, 18, 80, 91, 92, 109). Each method has its particular drawbacks that need to be addressed (56, 122).

Methodological issues. A disadvantage of most methods is that one CBF determination takes ~15 min (114). This renders such methods impractical for assessment of the rapid changes associated with postural cerebrovascular adjustment (18). Two methods that have the potential to provide for a continuous assessment of changes in CBF are the TCD-determined V_mean, e.g., of the middle cerebral artery (MCA), and the NIRS-derived changes in regional cO₂Hb. A critical issue is to what extent V_mean reflects volume flow. V_mean is calculated from the frequency distribution of the Doppler shifts, and it is assumed to represent flow velocity in the center of the vessel. In the unlikely case that flow is not laminar, V_mean changes out of proportion to flow. Also, changes in V_mean can be equated to flow only if both the angle of insonation and the vessel diameter at the site of investigation remain stable. The large cerebral arteries are conductance rather than resistance vessels, and changes in MAP within the physiological range appear to have negligible effects on the diameter of the insonated artery. More direct observations made during craniotomy reveal that the vessel diameter does not change significantly during variations in MAP of a magnitude that surpasses the changes manifest in response to orthostasis (42). Also, orthostatic stress, as simulated by LBNP, does not alter the diameter of the MCA as assessed with MR imaging (150), and changes in MCA V_mean seem to follow cerebral ¹³³Xe clearance (9, 23). Thus the constancy of the MCA diameter during postural stress relates changes in V_mean to those in CBF.

NIRS is based on the transparency of tissue to light in the near-infrared region, and the O₂ status-dependent changes in absorption in cerebral tissue caused by chromophores, i.e., mainly oxy- and deoxyhemoglobin (O₂Hb and HHb) (24, 109). With the use of a modified Lambert-Beer law, changes in light absorption at different wavelengths are measured and tissue oxygenation is monitored. NIRS follows changes in cerebral oxygenation in parallel with CBF as determined by ¹³³Xe clearance (15). In humans during carotid clamping and declamping, NIRS-determined cerebral cO₂Hb also compares satisfactorily with jugular bulb venous O₂ saturation (187). The cO₂Hb reflects the cerebral cortex at the measurement site only (3). Within the sampled volume, hemoglobin is contained in arterioles, capillaries, and venules, but the relative position of pigments determined by NIRS remains unknown. From anatomic studies of the brain, the venule to total vessel volume ratio ranges from 2/3 to 4/5 (8). Because ~5% of the blood is within the capillaries and ~20% in the arterioles, it may be argued that NIRS is dominated by the local venous O₂ saturation rather than a tissue O₂ content. Yet values of NIRS measured cO₂Hb are higher than internal jugular venous O₂ saturation (109), and NIRS differentiates fainters from nonfainters before the onset of the faint by the reduction in cO₂Hb (24). Comparable results have been obtained during LBNP studies (119). Hoshi et al. (63) isolated the cerebral from the systemic circulation in rats but maintained central and peripheral nervous systems intact, enabling uncoupling of regional cerebral O₂ metabolic rate and CBF. They provided evidence that cO₂Hb, at least in this animal model, is the most sensitive indicator of bidirectional changes in CBF. NIRS-determined cO₂Hb integrates the arterial O₂ content and the regional CBF, and, as established for skeletal muscle, NIRS obtains information on tissue oxygenation and metabolism beyond that obtained by venous blood sampling. Angulation of the optodes is of relevance with small interoptode distances (171). The depth of the measured tissue volume is a function of the interoptode distance (55, 109). From studies conducted during carotid surgery, the NIRS-determined cerebral oxygenation reflects the tissue oxygenation, provided that superficial tissue oxygenation is eliminated by spatial resolution (3). Caveats of cerebral NIRS include insufficient light shielding, optode displacement, and a sample volume including muscle or the frontal sinus mucous membrane (109). One approach to overcome the uncertainty of each of the methods is to combine TCD and NIRS because they are based on different physical principles, assuming that concordant changes indicate a change in regional CBF (3, 51, 107, 131, 173). A 50% reduction in MCA V_mean and a 10-15% reduction in cO₂Hb are associated with syncope (15, 24, 51, 90, 107, 116, 117).

The intravascular route provides the most accurate method to measure arterial pressure. It is, however, important to appreciate that, e.g., the radial artery may constrict with a ~6% reduction in diameter when under prolonged orthostatic stress and then dilates with appearance of (pre)syncopal symptoms (70). In the few patients in whom intracranial arterial pressures have been studied, the percentage of the original pulse pressure remaining in small cortical arteries was on average ~3% less than that remaining in the cervical carotid artery on occlusion of the common carotid artery (5). Thus also intra-arterial pressure may not fully reflect the pressure driving CBF in the large cerebral arteries. Noninvasive measurement of blood pressure as afforded by the Finapres device or other arterial volume clamping systems (2) may bear the same limitation and, in addition, vasoconstriction may affect the intra-arterial to finger pressure transfer. Also, the determination of the critical closing pressure (CrCP) as the pressure-axis intercept of instantaneous finger pressure-velocity relationships may be flawed by a ~70- to 100-ms time lag between the two waveforms, i.e., the additional time required for the pressure wave to reach the finger compared with the time it takes for it to reach the MCA. Dawson et al. (29), however, concluded that this parameter is not critical; without lag compensation, linear regression still produced values for CrCP significantly larger than zero. On a similar vein, arterial CO₂ is often inferred by either the end-tidal or the transcutaneous routes, which differ in their temporal resolution, and especially transcutaneous measurements of CO₂ may be sluggish. Also, the latency and time constant of the MCA V_mean response to changes in arterial CO₂ are to be taken into account (132).

Noninvasive or minimally invasive continuous tracking of changes in stroke volume (SV) and CO by bioimpedance, ultrasound, and arterial pulse-wave analysis has the potential to appreciate the importance of systemic blood flow for perfusion of the brain. As an example, modeling flow from arterial pressure by simulating a nonlinear three-element model of the aortic input impedance (180) has been applied to study changes in cerebral velocity and/or oxygenation and their relationship to changes in systemic hemodynamics (31, 51, 67, 69, 130, 131, 173). A possible shortcoming shared by all noninvasive methods is that if absolute values are needed, calibration against a method like phase-controlled quadruple thermodilution, Fick, or inert gas-rebreathing is necessary (72, 133, 173). After calibration, the tracking of changes in SV with Modelflow vs. a thermodilution-based estimate changes compared with within 5 ± 2% (mean ± SD) during prolonged HUT (53). If absolute values are not required, the method gives reliable trend data, and changes in CO can be tracked from an arterial pressure waveform that can be as peripheral as the radial artery (75, 180) or finger (53, 172). A general shortcoming is that validation of beat-to-beat tracking of SV is based on conventional measurements of SV like thermodilution-based estimates that are obtained as averages over at least some 20 heart beats (48, 73, 73) and do not reflect the beat-to-beat fluctuations, which may be considerable (166).

	CARDIOVASCULAR DYNAMICS IN ORTHOSTASIS

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

Central cardiovascular variables. On passive or active assumption of the upright position, the first circulatory event is a gravitational displacement of blood away from the thorax to dependent regions of the body with a fall in venous return (155). Depending on the type of orthostatic stress (i.e., active standing, LBNP, or HUT), 0.5 to 1 liter of blood is transferred to the regions below the diaphragm. Orthostatic pooling of venous blood begins immediately, and the total transfer is almost complete within 3-5 min depending on the investigated body region. In addition to this transfer of thoracic blood, the central blood volume is affected by transcapillary filtration of fluid into the interstitial spaces in the dependent parts of the body in response to the high capillary pressure with little interstitial counterpressure. Continued filtration into the tissue further reduces the circulating volume, although fluid is gained from the tissue above the venous hydrostatic indifference point (128), which is defined as the axial reference within the column of venous blood where pressure is not altered by postural reorientation (128). The pooled blood is not stationary, but in regions of the lower part of the body its transit time is prolonged (138). During 5 min of quiet standing, the hydrostatic load may induce a loss of ~400 ml of plasma water (103). The transcapillary loss of fluid approaches stability after ~20-30 min with a net fall in plasma volume of ~15%, but a steady state is not reached (108). As a consequence of blood pooling and the superimposed decline in plasma volume, the return of venous blood to the heart is reduced and central venous pressure (CVP) falls (173). The end-diastolic filling of the right ventricle is affected, which, in turn, leads to a reduction in SV and a ~20% fall in CO (53). Despite the fall in CO, MAP is preserved by compensatory vasoconstriction of resistance and capacitance vessels in the splanchnic, musculo(cutaneous), and renal vascular beds (138).

The circulatory adjustment to active standing up includes an initial ~30-s lasting fluctuation in MAP followed in 1-2 min by a phase of relative stability. Initially, MAP drops some 25 mmHg as total peripheral resistance falls ~40% for 6-8 s unrelated to orthostasis or straining. This transient fall in MAP is likely to explain the feelings of lightheadedness that even healthy humans sometimes experience shortly after standing up and may even cause recurrent syncope (Fig. 2; Refs. 157, 184). The rapid short-term adjustments to orthostatic stress are mediated exclusively by neural pathways of the autonomic nervous system. During prolonged orthostatic stress, additional adjustments are mediated by the humoral limb of the neuroendocrine system (i.e., renin-angiotensin-aldosterone system). The main sensory receptors involved in orthostatic neural reflex adjustments are the arterial mechanoreceptors (baroreceptors) located in the aortic arch and carotid sinuses. The most important defense against a critical reduction in central blood volume is that of muscle activity, and in everyday life extensive pooling is limited by activation of the skeletal muscle pump (108, 155, 162). Also in the upright moving position, maintenance of sufficient venous return is assisted by the circulatory effects of contracting muscles (7). If the muscle pump is not activated, it results in the syncope that even healthy humans experience (Fig. 3; Refs. 108, 160).

View larger version (16K): [in this window] [in a new window]   Fig. 2.   Cerebrovascular and hemodynamic response to standing (average of 10 subjects). Cardiovascular and cerebral perfusion and oxygenation responses to standing in healthy adults. Note the initial fall in middle cerebral artery mean flow velocity (Vmean) and near-infrared spectroscopy (NIRS)-determined cerebral oxygenation at standing up and the reduction after 5 min upright. MAPmca, mean arterial pressure at brain level; O2Hb, cerebral oxygenation; CO, cardiac output; TPR, total peripheral vascular resistance. [From Ref. 51, with permission.]

View larger version (16K): [in this window] [in a new window]   Fig. 3.   Probability of development of vasovagal syncope during passive head-up tilt. Sustained nonsyncope probability (Kaplan-Meier) curves for 79 subjects during 1 h of 50° head-up tilt and for 9 subjects during double-strop suspension with elevated legs. Sustained nonsyncope probabilities are different (P < 0.02). [From Ref. 108, with permission.]

Cerebral perfusion. The O₂ supply to the brain depends on the arterial O₂ content and the CBF of 50-60 ml · 100 g¹ · min¹. The cerebral O₂ uptake is ~3 ml · 100 g¹ · min¹, accounting for 15-20% of the basal metabolic rate (138). In healthy subjects, an acute lowering of CBF is associated with mild symptoms of cerebral hypoperfusion. Mental confusion becomes prominent with 50-60% reduction, and cerebral oxygenation becomes affected (107, 117).

Standing up places the brain in a most disadvantageous position. In the upright position, the cerebral arteries are positioned some 30 cm above the heart, whereas ~70% of the total blood volume shifts below that level (138). For the brain, not only its inflow pressure but also the venous and CSF pressures decline in proportion to the vertical distance to the heart (29, 44, 85, 137). A proposed, yet unproven, mechanism by which the surrounding pressure of the intracranial veins could affect CBF is by way of the vascular siphon model. The prerequisite for the existence of a siphon is a continuous column of blood in both the arterial and venous arms of the loop, and for the brain a siphon could exist from the thoracic aorta via the filled cerebral veins where they leave the skull to reach the right atrium. The idea is that in the upright position both arterial and venous pressure at brain level equally decrease, maintaining a gravitational pressure gradient across the siphon and thus over the brain. However, if the veins collapse (62), the gravitational pressure gradient within the veins no longer exists, violating the premise for a siphon effect (139). Hill and Barnard (61) concluded more than a century ago that the principle of the siphon effect was "entirely fallacious" because of the differences in distensibility and elasticity between the veins and the arteries, and there has not been much progress on that. When the brain becomes elevated above the heart, the veins above heart level collapse because the surrounding tissue pressure is greater than the pressure inside the veins, thus creating a Starling resistor effect (101, 138, 167). In a Starling resistor, mechanically modeled as an easily collapsible vascular segment submitted to an external pressure, blood flows when upstream pressure is sufficient to cause the pressure inside the collapsed segment to exceed the extravascular pressure and thus open the vessels (167). The upstream pressure at which the vessels collapse is often referred to as the CrCP. Thus CrCP represents the balance of cerebral vascular tone and extravascular, i.e., intracranial pressure (ICP; Refs. 29, 30).

Adaptation of CBF to orthostatic stress is conceptually linked to the CrCP (134, 147). In the rabbit, the relationship between CrCP and ICP is linear and CrCP decreases with arterial hypotension (134). Kongstad and Grände (85) demonstrated in the cat that an increase in venous pressure does not influence the tissue pressure for as long as the venous pressure remains below the tissue pressure. Only when the venous pressure equals the tissue pressure, collapse of the outflow vein disappears and the two pressures increase in parallel (85). This implies that for as long as there is a venous outflow resistance, the effect of venous pressure on ICP is minimal. Accordingly, Toung et al. (167) demonstrated in the dog that with the head at heart level, cerebral venous pressure (CRB_VP) rises linearly with the end-expiratory airway pressure. However, when the head is elevated, CRB_VP is affected only by a large increase in CVP. This indicates that jugular venous collapse serves as a resistance to the transmission of CVP to CRB_VP and supports that in the upright position a Starling resistor-type mechanism becomes operative (41, 167). These observations are consistent with the notion that the CrCP is under the influence of the cerebral venous outflow pressure and a variable venous outflow resistance (4, 85). In humans, CrCP is not readily assessed and a model approach of the instantaneous pressure-velocity relationship is used (1, 20, 29, 30, 182).

The effective downstream pressure may be derived from the zero-flow pressure as extrapolated by linear regression analysis of instantaneous V_mean-MAP relationships in which the pressure-axis intercept equals the theoretical CrCP (29, 30). During standing up, the rapid drop in CPP takes place too fast to be counterregulated. This makes the initial drop in CBF proportional to the driving pressure and explains the early fall in cerebral artery V_mean at ~7 s after standing up (Fig. 2). Data on local and sympathetic control of cerebral vessel diameter are unified in the "dual-control hypothesis." This hypothesis states that the pial arterial circulation comprises two resistances in series with extraparenchymal vessels under autonomic neural control and intraparenchymal vessels as the major cerebral vascular resistance bed governed primarily by metabolic and myogenic factors (113, 170).

Taken together, the cerebral circulation is considered to consist of the large cerebral arteries that passively follow changes in transmural pressure, the pial arterial circulation including two segments subject to different CA mechanisms (113, 170), and the venous cerebrovascular bed behaving as a Starling resistor (4, 41, 85, 167, 170).

	REGULATION OF CEREBRAL BLOOD FLOW

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

The relative constancy of the overall craniospinal volume ("the Monro-Kellie doctrine"; Refs. 79, 169), the cerebrovascular anatomy, and the variations in CPP related to the ever-changing position of the cerebral circulation relative to the heart make the intracranial hemodynamics during orthostasis extremely complex (110, 169). Control of cerebral perfusion is linked closely to regulation of the intracranial volume. Control of flow compromises the arterial cerebrovascular bed, the large cerebral veins, and the processes associated with production and reabsorption of CSF (44, 169). According to Poiseuille's law, CBF is determined by the CPP and the cerebrovascular conductance, or its reciprocal, cerebrovascular resistance (CVR) (1). The CPP is the difference between MAP at the level of the circle of Willis and ICP, and ICP, in turn, encompasses CVP and the CSF pressure. The variable resistance to flow is encountered in the cerebral arteriolar bed mainly; the major cerebral conductance arteries are in principle noncompliant and act merely as a conduit for the pulsatile arterial flow from the aorta to the brain (120). CBF is dynamically adjusted to changes in the perfusion pressure, the metabolic activity of the brain, humoral factors, and autonomic nerve activity (18).

A characteristic feature of the cerebral circulation is that CBF tends to remain relatively constant over a range of systemic blood pressures, termed CA. The actual range of pressures may vary between subjects (91, 92). CA secures CBF by modulation of vascular smooth muscle responses, effectively buffering changes in ICP at the background of the limited intracranial compliance (126). In the following sections, the local and systemic regulatory mechanisms that participate in CA are highlighted, and the behavior of CA during orthostasis and syncope is discussed.

Cerebral autoregulation: local control. The proposed mechanisms operating at the level of cerebral vascular smooth muscle tone include myogenic, metabolic, neural, and endothelial factors (126). The myogenic hypothesis suggests that cerebral vascular smooth muscles constrict or relax in response to, respectively, an increase or a decrease in the transmural pressure (the "Bayliss effect"; Refs. 6, 38, 39). Both Kontos et al. (86) and MacKenzie et al. (105) studied the responses of cerebral precapillary vessels to changes in MAP in the cat. Vessel responses were found to be size dependent and capable to adjust flow over most of the pressure range (41, 170). Changes in transmural pressure produce vasoconstriction by affecting the membrane electrical properties of MCA muscle (50). Nitric oxide influences basal cerebral vascular tone under normal conditions and mediates vascular responses to diverse stimuli including hypoxia-induced cerebral vasodilatation (35, 177). The metabolic hypothesis holds that CBF is controlled by metabolites with vasoactive properties, including CO₂, H⁺, potassium, adenosine, and calcitonin-gene-related peptide. Yet, although these substances have vasodilatory properties, for each of these metabolites studies with contradictory results have been reported (for review, see Ref. 126).

Cerebral autoregulation: autonomic effects. The sympathetic innervation to the cerebral vasculature is largely via the superior cervical ganglion (113). Stimulation or denervation of these nerves affects resting CBF only marginally (113, 126), but inconsistent effects on CBF as reported in animals may be attributed to both species differences and effects of anesthesia (18, 57, 71). Inactivation of neural traffic by neurotoxin does not affect the flow-pressure relationship in the cat cerebral vessels, and until recently the sympathetic nervous system was held to exert an only insignificant tonic influence on cerebral vessels under physiological conditions (18). Yet there are data that do not conform to that. First, in humans MCA V_mean decreases during unilateral trigeminal ganglion stimulation (178). Vice versa, as estimated with single-photon-emission computed tomography, CBF increases after stellate ganglionic blockade (168). Second, studies both in healthy subjects and in patients with cardiac insufficiency support the view that cerebral perfusion may be affected by sympathetically mediated cerebral vasoconstriction as a consequence of a reduction in CO. During dynamic exercise, MCA V_mean and cO₂Hb increase (58, 68, 76). However, this increase is attenuated or absent in patients with cardiac insufficiency (59) and in patients with atrial fibrillation (67). When during cycling the ability to increase CO is limited by cardioselective ₁-adrenergic blockade in healthy subjects, the increase in MCA V_mean is reduced (69). Taken together, these observations suggest that a reduced ability to increase CO induces peripheral vasoconstriction not only in working skeletal muscle (127) but also in the brain. Sympathetic blockade at the level of the neck blunts this pharmacologically induced limitation in the rise in V_mean (66), supporting an influence of sympathetic nerves on CBF in humans (143). Equally, in patients with severe heart failure, CBF is reduced substantially but increases after cardiac transplantation (47). Thus, in response to a decline in CO, an increased sympathetic drive may also contribute to cerebral vasoconstriction. As an example, in the standing position the decrease in blood pressure at the level of the brain is well within the CA range but the reduction in CO is substantial (~20%).

The postural decrease in cerebral artery V_mean and in cO₂Hb is not fully accounted for by the associated reduction in the arterial CO₂ tension (Pa_CO2; Refs. 98, 190), and the finding that steady-state CBF or MCA V_mean as cO₂Hb decrease on standing (Fig. 2) seems to be at odds with the traditional concept of CA, i.e., that CBF is relatively constant within a wide range of perfusion pressure (12, 51, 98, 99, 107, 112, 126, 130, 144, 147, 173, 190). Also diurnal changes in CO relate to MCA V_mean (31). In general, cerebral perfusion is independent of CO, for as long as MAP remains normal or almost normal. The mentioned observations support that cerebral perfusion depends on arterial inflow pressure but also suggest that CO is important. This is not unexpected when considering that the brain represents only 2% of the body mass but that it receives ~15% of CO (138). A limitation to all studies that relate changes in CBF, MAP, and CO is that it has not been possible to measure MAP at the MCA or other large intracranial vessels and V_mean is taken as "a surrogate" for CBF. Thus, when relating changes in measured variables that are supposed to reflect CBF, MAP, and CO, we may remain uncertain on what happens to the true cerebral perfusion pressure and blood flow.

CO₂. CO₂ is a potent vasodilator of cerebral vessels, and CBF increases with an increase in Pa_CO2 (97) independent of CA (1, 18, 54, 80, 92, 115, 132). Conversely, hypocapnia induces constriction of the smaller cerebral arteries. Effects of CO₂ on the myogenic response of CA depend on several factors, e.g., H⁺ concentration, perfusion pressure, and endothelial function (89, 115). In humans, the CO₂ chemoreflexes and arterial baroreflexes are intertwined at a variety of levels (60, 121). The caliber changes of the resistance vessels in response to CO₂ (the "CO₂ reactivity of the brain") interfere with CA (100, 169, 170). The limits of MAP within which CA operates are modified by sympathetic activity and by Pa_CO2 (126); i.e., CA becomes less effective as Pa_CO2 increases (54, 152). In subjects with orthostatic intolerance, hypocapnia may contribute to a reduction in MCA V_mean and cO₂Hb (51, 109, 118), whereas an increase in inspiratory CO₂ raises MCA V_mean and may improve orthostatic tolerance (10, 118).

Apart from its cerebrovascular effects, CO₂ exerts an influence on the systemic circulation that could provoke a syncope. Hypocapnia reduces arterial vascular resistance, resulting in a small reduction in MAP (16, 64, 121, 135). When autonomic cardiovascular reflexes are malfunctioning or absent, the systemic vasodilatory effects of hypocapnia become more obvious (121).

Static and dynamic components of autoregulation. CA needs to have both fast- and slow-acting regulatory components to span the range of prevailing demands on CBF in everyday life (1, 164). Dynamic CA refers to an ability to restore CBF in the face of MAP changes within seconds and reflects the latency of the cerebral vasoregulatory system (123). Static CA reflects the overall efficiency of the system. Accordingly, the classic CA curve represents the static behavior of the CA as quantified by time-domain-based analysis (123). The consequence of a latency of the CA mechanism is that brisk and short-lasting changes in pressure will be transmitted more or less unmodified to flow.

Methods proposed to assess the dynamic CA are based on analysis of oscillations in cerebral artery V_mean, most often in the MCA, either spontaneous or induced by short reductions or increments in MAP, in the time or frequency domain (24, 122, 164, 165). Frequency-domain methods classify CA according to the coherence, transfer function, and phase-frequency response between V_mean and MAP as assessed by spectral and cross-spectral analysis. Transfer gain increases substantially with frequencies from 0.07 to 0.20 Hz in association with a gradual decrease in phase (189). The many data thus obtained indicate that attenuation of oscillations in V_mean in response to changes in arterial pressure may be more effective at low than that at high frequencies and allow CA to be interpreted as a frequency-dependent phenomenon (34, 125, 189). As yet it is uncertain whether the various methodologies that claim to quantify the static and dynamic components of CA are interchangeable (122, 164).

In healthy subjects, variations in MCA V_mean precede variations in MAP at the spontaneously occurring oscillation in MAP at 0.1 Hz (34, 116, 189) and with a coherence that declines with frequency (125, 189). The phase-lead of MCA V_mean in advance of MAP and the frequency-related reduction in coherence are interpreted as the result of CA operating in this frequency range with the quality of a high-pass filter (34, 123, 189). At high frequencies, less cerebral attenuation of MAP oscillations to MCA V_mean implies that the CA cannot respond fast enough to rapid changes in MAP (123). The transient fall in MCA V_mean on standing up is an example of the slowness of CA adjustment (Fig. 2). Interestingly, the initial decline in MAP on standing is comparable for the young and the elderly, but the reduction in V_mean in older subjects is small, which was interpreted as indicative for enhanced CA in the elderly (99).

The lower limit of cerebral autoregulation. Lassen (91) reported that, below a certain limit, cerebral vessel diameter, CBF, and MAP change proportionally. In most studies, determination of CA is based on quantification of the complex relationship of CBF and MAP, the latter taken to represent CPP. CA is evaluated by pharmacological and physical manipulation of MAP, the latter often by deliberate pooling of blood by LBNP or by postural stress. Olsen et al. (119) determined the lower limit of CA (LLCA; Ref. 41) by reducing MAP to 50% of control by using labetolol infusion and LBNP. For the maintenance of sufficient cerebral perfusion in upright humans, the LLCA is of special interest. The LLCA is identified in a variety of anesthetized animals by bleeding (105) and in humans subjected to pharmacologically and/or posture-induced hypotension (90). The values found in both animals and humans vary, again attributable to species differences, use of anesthetic agents in many animal experiments, and the methodology used to elicit hypotension and to gauge the produced changes in CBF (41, 122). Patients with orthostatic hypotension related to sympathetic failure tolerate a reduction in MAP remarkably well, suggesting that the LLCA is not a fixed value and that it may shift toward a lower MAP (51, 163).

There is room for methodological concern in the evaluation of the LLCA in that the approaches used for its determination by decreasing MAP through bleeding, postural stress, and/or vasodilatation inevitably produce a concomitant reduction in CO. It should be considered that under these conditions, the effects of MAP and CO on CBF cannot be examined separately. As an example, when CO is rigorously controlled as is the case during cardiopulmonary bypass surgery, CBF is independent from CPP for a range of pressures (36, 114).

	STRAINING AND G FORCE: IMPACT ON CEREBRAL PERFUSION

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

In the standing position, straining is highly effective in inducing a syncope. Power lifting may occasionally lead to dizziness and even to fainting, suggesting that especially in the upright position CBF is compromised. Syncope is reported for weight lifting when the intrathoracic pressure increases to ~160 mmHg (25). The concomitant elevation in CVP during intensive exercise may protect cerebral perfusion by counteracting the rise in MAP (131), although MCA V_mean decreases during heavy resistance training (32). The weight lifters' blackout (25), like self-induced syncope (64, 96), may be attributed to a critical reduction in CBF due to preexercise hyperventilation (33). Equally, a syncope is observed occasionally during playing of wind instruments (13). Intense expiratory strain with a nonphysiological elevation of CVP is likely to cause a critical reduction in CPP.

In supine humans, intracranial tissue pressure approximates CVP, and an elevation in CVP by straining would induce a parallel increase in the cerebral outflow pressure. During straining in the supine position, there is indeed a close relation between MCA V_mean and the MAP-to-CVP difference as an indication of CPP (130). This is, however, not so during standing, and by standing the small influence of a 40-mmHg elevation in CVP for cerebral outflow pressure could reflect a collapse of outflow resistance veins (4). During straining, the changes in MCA V_mean are of a greater magnitude than those established in MAP. This may indicate either a delay in activation of the CA or the inability of CA to cope with the magnitude and speed of the changes in MAP. Dawson et al. (29) proposed that the large drop in CrCP at the end of straining reduces CVR and explains the large increase in MCA V_mean. Also during prolonged coughing, intrathoracic and abdominal pressures are transmitted via the great veins to the intracranial compartment (49), causing a transiently elevated pressure with a critical impairment of CBF and syncope (111, 153).

G force. During exposure to +G_z, loss of consciousness occurs in aircrew flying high-performance aircraft. This phenomenon is responsible for several aircraft losses with accompanying loss of life since 1938 (17). In a recent survey among jet pilots flying fighter aircrafts with rapid-onset rates, a minority reported G-induced loss of consciousness, although almost all had experienced +G_z-related grayouts and/or blackouts to the high sustained +G_z forces (188), and an in-flight reduction of cO₂Hb during aerial gunnery training missions has been demonstrated (83).

	ORTHOSTATIC INTOLERANCE AND COUNTERMEASURES

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

Postural stress by relaxed standing or passive HUT may reduce orthostatic tolerance in healthy subjects who otherwise never faint. In both young and elderly subjects with no history of fainting, addition of invasive instrumentation during prolonged HUT increases the incidence of a vasovagal syncope (74). It should also be considered that vasovagal responses are not necessarily abnormal; the as-yet-unidentified neural pathways involved in the response are probably present in all healthy humans with individual differences in susceptibility (175). The medical history in suspected vasovagal syncope is essential, and tilt-table testing is mainly useful to confirm the diagnostic suspicion.

The functional derangement in vasovagal syncope is a withdrawal of muscle sympathetic nerve activity with strong evidence for an early loss of vasomotor tone in the majority of fainting subjects (175). In healthy volunteers subjected to prolonged HUT, Madsen et al. (106) demonstrated that cerebral perfusion is maintained by peripheral vasoconstriction in muscle and skin until the onset of vasovagal syncope when muscle perfusion becomes increased at the expense of blood flow to the brain. Many of the premonitory symptoms of a vasovagal syncope are indicative for cerebral hypoperfusion (118). However, with respect to the index used to infer CVR, controversies exist regarding interpretation of TCD before and during a syncope (20, 147). The pulsatility index [PI; (systolic velocity  diastolic velocity)/mean velocity] is proposed as a parameter of downstream cerebrovascular resistance but has not been evaluated for this purpose. PI does not take into account the prevailing level of blood pressure, and Czosnyka et al. (26) restrained its value as an index of CVR for as long as BP and HR are relatively stable. At syncope, while MAP falls, diastolic and mean cerebral and carotid blood flow velocities diminish, whereas the fall in systolic velocity is limited (Fig. 4; Ref. 84). During a vasovagal syncope, PI vs. CVR, expressed as the ratio of MAP to MCA V_mean, may provide conflicting results with a decrease in CVR but a rise in PI (20, 77, 147). Some have considered the increase in PI to reflect defective CA (46), whereas others have interpreted the reduction in CVR to indicate that CA is intact at the appearance of a syncope (147). The reduction in diastolic flow velocity during a syncope (Fig. 1), even becoming zero, may be interpreted as a collapse of downstream vessels when the diastolic blood pressure decreases below the CrCP of the cerebral vessels (20, 77, 147). Also calculation of CVR as the ratio of the pressure drop to flow across the vascular bed is complicated by the difficulty in directly determining the pressure drop because the values of ICP and CBR_VP are unknown (65). With orthostatic stress, the assumption of a constant intracranial or venous pressure may be flawed and, if so, in the upright position MAP/MCA V_mean does not provide the same information about CVR as when supine (65, 182). Alternative methods to interpret changes in CVR such as an estimate of CrCP or the inverse of the CrCP-regression slope, the resistance-area product, are proposed (20, 123). Accounting for CrCP in the estimation of CVR may provide a more physiological explanation for the temporal relationship between MAP and V_mean during rapid changes in MAP (20, 21, 29, 65, 142, 181).

View larger version (27K): [in this window] [in a new window]   Fig. 4.   Cerebrovascular and hemodynamic responses in postural tachycardia syndrome and vasovagal fainting. A: a 33-yr-old woman with history of orthostatic dizziness and palpitations. Presyncopal symptoms coincide with an excessive reduction in mean middle cerebral artery blood flow velocity (CBFV) and CO but no decrease in mean blood pressure (BP). B: a 21-yr-old woman subjected to prolonged postural stress who gradually develops vasovagal fainting. At the faint, CBFV declines together with BP, TPR, and heart rate (HR). CBFV, middle cerebral artery blood flow velocity; bpm, beats/min. Bars, standing. * Presyncopal complaints. [Modified from Ref. 52, with permission.]

Differences in the postural circulatory adaptation between subjects who faint vs. those who do not are subtle and do not permit to predict the occurrence of fainting (161). Subjects with orthostatic intolerance or postural tachycardia syndrome, however, present with a disproportionately greater effect of postural stress on HR and CO than on MAP. This has been attributed to an abnormal functional distribution of central sympathetic tone to the heart and vasculature (40, 158). Some individuals who are orthostatically intolerant maintain a normal MAP, and, in the absence of systemic hypotension, a reduction in MCA V_mean may even result in syncope (Fig. 4; Refs. 46, 52, 102, 151). In these patients, a symptomatic reduction in MCA V_mean during standing is a consistent finding and may reflect the adjustment to a critically limited CO (46, 52, 102, 118, 147).

During maximal hyperventilation, MCA V_mean may fall ~55% (82, 118). Controversy exists as to whether the decrease in MCA V_mean results from excessive sympathetic outflow to the cerebral vasculature (146) or from hyperventilation-induced hypocapnia (88) that may affect CrCP and CVR (1, 27, 124). A link between the postural decline in MCA V_mean and CO₂ was demonstrated by Cencetti et al. (22), but the contribution of the decrease in CO₂ to the reduction in MCA V_mean is as yet undefined. The finding that at 30 mmHg LBNP CO₂ does not change but V_mean becomes reduced suggests that CO₂ does not fully account for the postural reduction in MCA V_mean (190). CO₂ levels and indexes of cerebrovascular resistance decrease during presyncope, and CrCP may increase to levels approaching MCA diastolic blood pressure before decreasing precipitously on syncope (20).

Similarly, the interpretation of the data on dynamic CA in presyncopal subjects, as gauged in the time and frequency domain, is under dispute (123, 148, 190). Data from temporal sequence analysis suggest that during fainting changes in V_mean precede the fall in MAP (28), but this may equally be explained by the concomitant effects of a presyncopal decline in CO₂. In healthy subjects during LBNP, the reduction in steady-state V_mean together with the increase in transfer function gain of MAP to V_mean is interpreted to indicate a deterioration of CA and a possible contribution to the development of a (pre)syncope (190). However, in subjects with recurrent vasovagal syncope provoked by HUT, dynamic CA does not differ from that of controls (20, 148). Considering that a postural reduction in MCA V_mean as in cO₂Hb in humans is the rule, these findings may be interpreted as being the result of the intrinsic adaptive responses of a functioning dynamic CA to a sometimes critical postural reduction in CO rather than to a malfunctioning of CA per se (52).

Countermeasures. Several approaches have been advocated to alleviate symptoms in patients with orthostatic intolerance, including drug treatment, volume expansion, physical countermaneuvers, and endurance training. Subjects with orthostatic intolerance should be warned to avoid immobility and encouraged to increase their leg muscle mass because even moderate training improves orthostatic tolerance in deconditioned subjects (145). Exercise also promotes retention of fluid in the upright posture (104). When considering that pooling of blood is the major cause in the development of orthostatic intolerance, maneuvers that counteract this transfer of blood are beneficial. Raising muscle tension of the legs attenuates the decrease in MAP generated by LBNP (156). In patients with sympathetic failure, leg muscle tensing increases MAP and reduces symptoms of orthostatic intolerance (174). In healthy subjects with normal orthostatic tolerance, leg tensing does not affect MAP but elevates CVP and CO and attenuates the postural reduction in MCA V_mean as in cO₂Hb (162, 173). Leg tensing can also abort an imminent faint (Fig. 5; Ref. 87).

View larger version (29K): [in this window] [in a new window]   Fig. 5.   Effects of leg tensing on cerebral perfusion. Leg tensing at imminent syncope enhances cerebral blood flow velocity and oxygenation. MCAV, middle cerebral artery blood flow velocity.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

During standing, cerebral autoregulation is challenged by the position of the cerebral circulation through the reduction in arterial inflow pressure, cerebral perfusion pressure, and cardiac output. A syncope is mostly associated with the upright position. Vasovagal responses, cardiac arrhythmias, and autonomic failure are the common causes. The most important defense against a critical reduction in the central blood volume is that of the muscle pump and, if it is not used, even normal humans faint shortly after standing. Continuous tracking of CBF velocity by TCD and NIRS-determined cerebral tissue oxygenation have contributed to the understanding of the cerebrovascular adjustments to postural stress in health and disease; e.g., MAP does not necessarily reflect the cerebrovascular phenomena associated with a (pre)syncope. Studies on dynamic CA in presyncope that take into account both MAP and V_mean indicate a decrease in cerebrovascular resistance with a complex interplay between vasoconstriction and vasodilatation preceding a syncope. The dynamic component of CA is assessed by methods that are based on analysis of oscillations in MCA V_mean related to MAP in the time or frequency domain. CA may be interpreted as a frequency-dependent phenomenon, with less cerebral attenuation of MAP oscillations to MCA V_mean at high frequencies. The clinical implication is that the CA cannot respond fast enough to rapid changes in MAP, as seen in the transient fall in MCA V_mean on standing up. It is as yet uncertain to what extent in the earlier stages of (pre)syncope with MAP still within CA limits, the (pre)syncopal reduction in cerebral perfusion and oxygenation results from excessive sympathetic outflow to the cerebral vasculature or from hyperventilation-induced hypocapnia. When a syncope progresses, it is the fall in MAP below the lower limit of CA that reduces cerebral perfusion and oxygenation further to unconsciousness. In subjects with recurrent vasovagal syncope, dynamic CA seems not different from that of healthy controls. Redistribution of CO may affect cerebral perfusion by increased cerebral vascular resistance, supporting the view that cerebral perfusion depends on arterial inflow pressure given a sufficient CO.

	ACKNOWLEDGEMENTS

This work was supported by grants from the Netherlands Heart Foundation (NR. 99-182) and the Danish National Research Foundation (504-14).

	FOOTNOTES

¹ Syncope (Gr): -o = to beat together; collaps (Lat): collabor, -lapsus sum = to collapse.

Address for reprint requests and other correspondence: J. J. van Lieshout, Academic Medical Center, Univ. of Amsterdam, Dept. of Internal Medicine, F4-264, PO Box 22700, 1100 DE Amsterdam, The Netherlands (E-mail: j.j.vanlieshout{at}amc.uva.nl).

10.1152/japplphysiol.00260.2002

	REFERENCES

TOP ABSTRACT INTRODUCTION SEQUENCE OF CLINICAL EVENTS CEREBRAL BLOOD FLOW AND... CARDIOVASCULAR DYNAMICS IN... REGULATION OF CEREBRAL BLOOD... STRAINING AND G FORCE:... ORTHOSTATIC INTOLERANCE AND... CONCLUSIONS REFERENCES

1.   Aaslid, R. Cerebral hemodynamics. In: Transcranial Doppler, edited by Newell DW, and Aaslid R.. New York: Raven, 1992, p. 49-55.

2.   Aaslid, R, Lindegaard KF, Sorteberg W, and Nornes H. Cerebral autoregulation dynamics in humans. Stroke 20: 45-52, 1989[Abstract/Free Full Text].

3.   Al-Rawi, PG, Smielewski P, and Kirkpatrick PJ. Evaluation of a near-infrared spectrometer (NIRO 300) for the detection of intracranial oxygenation changes in the adult head. Stroke 32: 2492-2500, 2001[Abstract/Free Full Text].

4.   Asgeirsson, B, and Grände PO. Local vascular responses to elevation of an organ above the heart. Acta Physiol Scand 156: 9-18, 1996[Web of Science][Medline].

5.   Bakay, L, and Sweet WH. Cervical and intracranial intra-arterial pressures with and without vascular occlusion. Surg Gynecol Obstet 95: 67-75, 1952[Web of Science][Medline].

6.   Bayliss, WM. On the local reaction of the arterial wall to changes of internal pressure. J Physiol 28: 220-231, 1902[Free Full Text].

7.   Beecher, HK, Field ME, and Krogh A. The effect of walking on the venous pressure at the ankle. Skand Arch Physiol 73: 133-141, 1935.

8.   Bevan, JA. Cerebral arterial behavior providing constant cerebral blood flow, pressure, and volume. In: Arterial Behavior and Blood Circulation in the Brain, edited by McHedlishvili G.. New York: Plenum, 1986, p. 42-95.

9.   Bishop, CC, Powell S, Rutt D, and Browse NL. Transcranial Doppler measurement of middle cerebral artery blood flow velocity: a validation study. Stroke 17: 913-915, 1986[Abstract/Free Full Text].

10.   Blaber, AP, Bondar RL, Moradshahi P, Serrador JM, and Hughson RL. Inspiratory CO₂ increases orthostatic tolerance during repeated tilt. Aviat Space Environ Med 72: 985-991, 2001[Medline].

11.   Bleasdale-Barr, KM, and Mathias CJ. Neck and other muscle pains in autonomic failure: their association with orthostatic hypotension. J R Soc Med 91: 355-359, 1998[Abstract].

12.   Bode, H. Cerebral blood flow velocities during orthostasis and physical exercise. Eur J Pediatr 150: 738-743, 1991[Web of Science][Medline].

13.   Borgia, JF, Horvath SM, Dunn FR, von Phul PV, and Nizet PM. Some physiological observations on French horn musicians. J Occup Med 17: 696-701, 1975[Web of Science][Medline].

14.   Brignole, M, Alboni P, Benditt D, Bergfeldt L, Blanc JJ, Bloch TP, Fitzpatrick A, Hohnloser S, Kapoor W, Kenny RA, Theodorakis G, Kulakowski P, Moya A, Raviele A, Sutton R, Wieling W, Janousek J, and van Dijk G. Task force on syncope, European Society of Cardiology. Part 1. The initial evaluation of patients with syncope. Europace 3: 253-260, 2001[Free Full Text].

15.   Bucher, HU, Edwards AD, Lipp AE, and Duc G. Comparison between near infrared spectroscopy and ¹³³Xenon clearance for estimation of cerebral blood flow in critically ill preterm infants. Pediatr Res 33: 56-60, 1993[Web of Science][Medline].

16.   Burnum, JF, Hickam JB, and McIntosh HD. The effect of hypocapnia on arterial blood pressure. Circulation 9: 89-95, 1954[Web of Science][Medline].

17.   Burton, RR, and Whinnery JE. Operational G-induced loss of consciousness: something old; something new. Aviat Space Environ Med 56: 812-817, 1985[Medline].

18.   Busija, DW, and Heistad DD. Factors involved in the physiological regulation of the cerebral circulation. Rev Physiol Biochem Pharmacol 101: 161-211, 1984[Web of Science][Medline].

19.   Calkins, H, Shyr Y, Frumin H, Schork A, and Morady F. The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and neurocardiogenic syncope. Am J Med 98: 365-373, 1995[Web of Science][Medline].

20.   Carey, BJ, Eames PJ, Panerai RB, and Potter JF. Carbon dioxide, critical closing pressure and cerebral haemodynamics prior to vasovagal syncope in humans. Clin Sci (Lond) 101: 351-358, 2001[Medline].

21.   Carey, BJ, Manktelow BN, Panerai RB, and Potter JF. Cerebral autoregulatory responses to head-up tilt in normal subjects and patients with recurrent vasovagal syncope. Circulation 104: 898-902, 2001[Abstract/Free Full Text].

22.   Cencetti, S, Bandinelli G, and Lagi A. Effect of PCO₂ changes induced by head-upright tilt on transcranial Doppler recordings. Stroke 28: 1195-1197, 1997[Abstract/Free Full Text].

23.   Clark, JM, Skolnick BE, Gelfand R, Farber RE, Stierheim M, Stevens WC, Beck GJ, and Lambertsen CJ. Relationship of ¹³³Xe cerebral blood flow to middle cerebral arterial flow velocity in men at rest. J Cereb Blood Flow Metab 16: 1255-1262, 1996[Web of Science][Medline].

24.   Colier, WNJM, Binkhorst RA, Hopman MT, and Oeseburg B. Cerebral and circulatory haemodynamics before vasovagal syncope induced by orthostatic stress. Clin Physiol 17: 83-94, 1997[Web of Science][Medline].

25.   Compton, D, Hill PM, and Sinclair JD. Weight-lifters' blackout. Lancet 2: 1234-1237, 1973[Web of Science][Medline].

26.   Czosnyka, M, Richards HK, Whitehouse HE, and Pickard JD. Relationship between transcranial Doppler-determined pulsatility index and cerebrovascular resistance: an experimental study. J Neurosurg 84: 79-84, 1996[Web of Science][Medline].

27.   Czosnyka, M, Smielewski P, Piechnik S, Al-Rawi PG, Kirkpatrick PJ, Matta BF, and Pickard JD. Critical closing pressure in cerebrovascular circulation. J Neurol Neurosurg Psychiatry 66: 606-611, 1999[Abstract/Free Full Text].

28.   Dan, D, Hoag JB, Ellenbogen KA, Wood MA, Eckberg DL, and Gilligan DM. Cerebral blood flow velocity declines before arterial pressure in patients with orthostatic vasovagal presyncope. J Am Coll Cardiol 39: 1039-1045, 2002[Abstract/Free Full Text].

29.   Dawson, SL, Panerai RB, and Potter JF. Critical closing pressure explains cerebral hemodynamics during the Valsalva maneuver. J Appl Physiol 86: 675-680, 1999[Abstract/Free Full Text].

30.   Dewey, RC, Pieper HP, and Hunt WE. Experimental cerebral hemodynamics. Vasomotor tone, critical closing pressure, and vascular bed resistance. J Neurosurg 41: 597-606, 1974[Web of Science][Medline].

31.   Diamant, M, Harms MPM, Immink RV, Van Lieshout JJ, and Van Montfrans GA. Twenty-four-hour non-invasive monitoring of systemic haemodynamics and cerebral blood flow velocity in healthy humans. Acta Physiol Scand 174: 1-9, 2002[Web of Science][Medline].

32.   Dickerman, RD, McConathy WJ, Smith GH, East JW, and Rudder L. Middle cerebral artery blood flow velocity in elite power athletes during maximal weight-lifting. Neurol Res 22: 337-340, 2000[Web of Science][Medline].

33.   Diehl, RR, Linden D, Bunger B, Schafer M, and Berlit P. Valsalva-induced syncope during apnea diving. Clin Auton Res 10: 343-345, 2000[Web of Science][Medline].

34.   Diehl, RR, Linden D, Lucke D, and Berlit P. Phase relationship between cerebral blood flow velocity and blood pressure. A clinical test of autoregulation. Stroke 26: 1801-1804, 1995[Abstract/Free Full Text].

35.   Faraci, FM, and Brian JEJ Nitric oxide and the cerebral circulation. Stroke 25: 692-703, 1994[Abstract].

36.   Feddersen, K, Aren C, Nilsson NJ, and Radegran K. Cerebral blood flow and metabolism during cardiopulmonary bypass with special reference to effects of hypotension induced by prostacyclin. Ann Thorac Surg 41: 395-400, 1986[Abstract].

37.   Fenton, AM, Hammill SC, Rea RF, Low PA, and Shen WK. Vasovagal syncope. Ann Intern Med 133: 714-725, 2000[Abstract/Free Full Text].

38.   Fog, M. Cerebral circulation. The reaction of the pial arteries to a fall in blood pressure. Arch Neurol Psychiatry 37: 351-364, 1937[Abstract/Free Full Text].

39.   Folkow, B. Description of the myogenic hypothesis. Circ Res 15: 279-287, 1964[Web of Science][Medline].

40.   Furlan, R, Jacob G, Snell M, Robertson D, Porta A, Harris P, and Mosqueda-Garcia R. Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation 98: 2154-2159, 1998[Abstract/Free Full Text].

41.   Gao, E, Young WL, Pile-Spellman J, Ornstein E, and Ma Q. Mathematical considerations for modeling cerebral blood flow autoregulation to systemic arterial pressure. Am J Physiol Heart Circ Physiol 274: H1023-H1031, 1998[Abstract/Free Full Text].

42.   Giller, CA, Bowman G, Dyer H, Mootz L, and Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery 32: 737-741, 1993[Web of Science][Medline].

43.   Graham, LA, and Kenny RA. Clinical characteristics of patients with vasovagal reactions presenting as unexplained syncope. Europace 3: 141-146, 2001[Abstract/Free Full Text].

44.   Grände, PO, Asgeirsson B, and Nordstrom CH. Physiologic principles for volume regulation of a tissue enclosed in a rigid shell with application to the injured brain. J Trauma 42: S23-S31, 1997[Web of Science][Medline].

45.   Greenfield, ADM An emotional faint. Lancet 1: 1302-1303, 1951[Medline].

46.   Grubb, BP, Samoil D, Kosinski D, Wolfe D, Brewster P, Elliott L, and Hahn H. Cerebral syncope: loss of consciousness associated with cerebral vasoconstriction in the absence of systemic hypotension. Pacing Clin Electrophysiol 21: 652-658, 1998[Medline].

47.   Gruhn, N, Larsen FS, Boesgaard S, Knudsen GM, Mortensen SA, Thomsen G, and Aldershvile J. Cerebral blood flow in patients with chronic heart failure before and after heart transplantation. Stroke 32: 2530-2533, 2001[Abstract/Free Full Text].

48.   Hamilton, WF. Comparison of the Fick and dye-injection methods of measuring the cardiac output in man. Am J Physiol 153: 309-321, 1948[Free Full Text].

49.   Hamilton, WF, Woodbury RA, and Harper HT. Arterial, cerebrospinal and venous pressures in man during cough and strain. Am J Physiol 141: 42-50, 1943.

50.   Harder, DR. Pressure-dependent membrane depolarization in cat middle cerebral artery. Circ Res 55: 197-202, 1984[Abstract/Free Full Text].

51.   Harms, MPM, Colier WNJM, Wieling W, Lenders JW, Secher NH, and Van Lieshout JJ. Orthostatic tolerance, cerebral oxygenation, and blood velocity in humans with sympathetic failure. Stroke 31: 1608-1614, 2000[Abstract/Free Full Text].

52.   Harms, MPM, and Van Lieshout JJ. Cerebrovascular and cardiovascular responses associated with orthostatic intolerance and tachycardia. Clin Auton Res 11: 35-38, 2001[Web of Science][Medline].

53.   Harms, MPM, Wesseling KH, Pott F, Jenstrup M, Van Goudoever J, Secher NH, and Van Lieshout JJ. Continuous stroke volume monitoring by modelling flow from non-invasive measurement of arterial pressure in humans under orthostatic stress. Clin Sci (Lond) 97: 291-301, 1999[Medline].

54.   Harper, AM, and Glass HI. Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cerebral cortex at normal and low arterial blood pressures. J Neurol Neurosurg Psychiatry 28: 449-452, 1965[Free Full Text].

55.   Harris, DN, Bailey SM, Cowans F, and Wertheim D. Effect of optode separation on brain penetration in adults. Adv Exp Med Biol 388: 133-135, 1996[Medline].

56.   Heistad, DD, and Kontos HA. Cerebral circulation. In: Handbook of Physiology. The Cardiovascular System. Peripheral Circulation and Organ Blood Flow. Bethesda, MD: Am. Physiol. Soc, 1983, vol. III, p. 137-182, sect. 2, pt. 1, chapt. 5.

57.   Heistad, DD, Marcus ML, and Gross PM. Effects of sympathetic nerves on cerebral vessels in dog, cat, and monkey. Am J Physiol Heart Circ Physiol 235: H544-H552, 1978[Abstract/Free Full Text].

58.   Hellstrøm, G, Fischer-Colbrie W, Wahlgren NG, and Jogestrand T. Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise. J Appl Physiol 81: 413-418, 1996[Abstract/Free Full Text].

59.   Hellstrøm, G, Magnusson G, Wahlgren NG, and Saltin B. Physical exercise may impair cerebral perfusion in patients with chronic heart failure. Cardiol Elderly 4: 191-194, 1996.

60.   Henry, RA, Lu IL, Beightol LA, and Eckberg DL. Interactions between CO₂ chemoreflexes and arterial baroreflexes. Am J Physiol Heart Circ Physiol 274: H2177-H2187, 1998[Abstract/Free Full Text].

61.   Hill, L, and Barnard H. The influence of the force of gravity on the circulation. Part II. J Physiol 22: 323-352, 1897.

62.   Holt, JP. The collapse factor in the measurement of venous pressure. Am J Physiol 134: 292-299, 1941[Free Full Text].

63.   Hoshi, Y, Kobayashi N, and Tamura M. Interpretation of near-infrared spectroscopy signals: a study with a newly developed perfused rat brain model. J Appl Physiol 90: 1657-1662, 2001[Abstract/Free Full Text].

64.   Howard, P, Leathart GL, Dornhorst AC, and Sharpey-Schafer EP. The "mess trick" and the "fainting lark." Br Med J ii: 382-384, 1951.

65.   Hughson, RL, Edwards MR, O'Leary DD, and Shoemaker JK. Critical analysis of cerebrovascular autoregulation during repeated head-up tilt. Stroke 32: 2403-2408, 2001[Abstract/Free Full Text].

66.   Ide, K, Boushel R, Sorensen HM, Fernandes A, Cai Y, Pott F, and Secher NH. Middle cerebral artery blood velocity during exercise with beta-1 adrenergic and unilateral stellate ganglion blockade in humans. Acta Physiol Scand 170: 33-38, 2000[Web of Science][Medline].

67.   Ide, K, Gulløv AL, Pott F, Van Lieshout JJ, Koefoed BG, Petersen P, and Secher NH. Middle cerebral artery blood velocity during exercise in patients with atrial fibrillation. Clin Physiol 19: 284-289, 1999[Web of Science][Medline].

68.   Ide, K, Horn A, and Secher NH. Cerebral metabolic response to submaximal exercise. J Appl Physiol 87: 1604-1608, 1999[Abstract/Free Full Text].

69.   Ide, K, Pott F, Van Lieshout JJ, and Secher NH. Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass. Acta Physiol Scand 162: 13-20, 1998[Web of Science][Medline].

70.   Iversen, HK, Madsen P, Matzen S, and Secher NH. Arterial diameter during central volume depletion in humans. Eur J Appl Physiol 72: 165-169, 1995[Web of Science].

71.   James, IM, Millar RA, and Purves MJ. Observations on the extrinsic neural control of cerebral blood flow in the baboon. Circ Res 25: 77-93, 1969[Abstract/Free Full Text].

72.   Jansen, JR, Schreuder JJ, Mulier JP, Smith NT, Settels JJ, and Wesseling KH. A comparison of cardiac output derived from the arterial pressure wave against thermodilution in cardiac surgery patients. Br J Anaesth 87: 212-222, 2001[Abstract/Free Full Text].

73.   Jansen, JRC, and Versprille A. Improvement of cardiac output estimation by the thermodilution method during mechanical ventilation. Intensive Care Med 12: 71-79, 1986[Web of Science][Medline].

74.   Jellema, WT, Imholz BPM, Van Goudoever J, Wesseling KH, and Van Lieshout JJ. Finger arterial versus intrabrachial pressure and continuous cardiac output during head-up tilt testing in healthy subjects. Clin Sci (Lond) 91: 193-200, 1996[Medline].

75.   Jellema, WT, Wesseling KH, Groeneveld AB, Stoutenbeek CP, Thijs LG, and Van Lieshout JJ. Continuous cardiac output in septic shock by simulating a model of the aortic input impedance: a comparison with bolus injection thermodilution. Anesthesiology 90: 1317-1328, 1999[Web of Science][Medline].

76.   Jørgensen, LG, Perko M, Hanel B, Schroeder TV, and Secher NH. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans. J Appl Physiol 72: 1123-1132, 1992[Abstract/Free Full Text].

77.   Jørgensen, LG, Perko M, Perko G, and Secher NH. Middle cerebral artery velocity during head-up tilt induced hypovolaemic shock in humans. Clin Physiol 13: 323-336, 1993[Medline].

78.   Kapoor, WN. Syncope. N Engl J Med 343: 1856-1862, 2000[Free Full Text].

79.   Kellie, G. On death from cold, and on congestion of the brain. Transactions of the Medico-Chirurgical Society of Edinburgh 1: 84-169, 1822.

80.   Kety, SS, and Schmidt CF. The effects of active and passive hyperventilation on cerebral blood flow, cerebral oxygen consumption, cardiac output, and blood pressure of normal young men. J Clin Invest 25: 107-112, 1946[Web of Science][Medline].

81.   Klein, LJ, Saltzman HA, Heyman A, and Sieker HO. Syncope induced by the Valsalva maneuver. A study of the effects of arterial blood gas tensions, glucose concentration and blood pressure. Am J Med 37: 263-268, 1964[Web of Science][Medline].

82.   Knappertz, VA, Rothacher G, Sievers C, Kramer G, Kubler A, Lehnert H, and Tegeler CH. Control for carbon dioxide-related changes in flow velocity by transcranial Doppler monitoring. J Neuroimaging 4: 137-140, 1994[Medline].

83.   Kobayashi, A, and Miyamoto Y. In-flight cerebral oxygen status: continuous monitoring by near-infrared spectroscopy. Aviat Space Environ Med 71: 177-183, 2000[Medline].

84.   Kojo, M, Wada M, Akiyoshi K, Inutsuka M, and Izumi T. Reduction of carotid artery blood flow in pediatric patients with syncope: evaluation with head-up tilt test. Neuropediatrics 32: 169-175, 2001[Web of Science][Medline].

85.   Kongstad, L, and Grände PO. The role of arterial and venous pressure for volume regulation of an organ enclosed in a rigid compartment with application to the injured brain. Acta Anaesthesiol Scand 43: 501-508, 1999[Web of Science][Medline].

86.   Kontos, HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, and Patterson JLJ Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol Heart Circ Physiol 234: H371-H383, 1978[Abstract/Free Full Text].

87.   Krediet, CTP, Van Dijk N, Linzer M, Van Lieshout JJ, and Wieling W. Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation 106: 1684-1689, 2002[Abstract/Free Full Text].

88.   Lagi, A, Cencetti S, Corsoni V, Georgiadis D, and Bacalli S. Cerebral vasoconstriction in vasovagal syncope: any link with symptoms? A transcranial Doppler study. Circulation 104: 2694-2698, 2001[Abstract/Free Full Text].

89.   Lambertsen, CJ, Semple SJG, Smyth MG, and Gelfand R. H⁺ and PCO₂ as chemical factors in respiratory and cerebral circulatory control. J Appl Physiol 16: 473-484, 1961[Abstract/Free Full Text].

90.   Larsen, FS, Olsen KS, Hansen BA, Paulson OB, and Knudsen GM. Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation. Stroke 25: 1985-1988, 1994[Abstract].

91.   Lassen, NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 39: 183-238, 1959[Free Full Text].

92.   Lassen, NA. Autoregulation of cerebral blood flow. Circ Res 15: 201-204, 1964[Web of Science][Medline].

93.   Leftheriotis, G, Dupuis JM, and Victor J. Cerebral hemodynamics in carotid sinus syndrome and atrioventricular block. Am J Cardiol 86: 504-508, 2000[Web of Science][Medline].

94.   Lempert, T. Recognizing syncope: pitfalls and surprises. J R Soc Med 89: 372-375, 1996[Abstract].

95.   Lempert, T, Bauer M, and Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 36: 233-237, 1994[Web of Science][Medline].

96.   Lempert, T, and von Brevern M. The eye movements of syncope. Neurology 46: 1086-1088, 1996[Abstract/Free Full Text].

97.   Lennox, WG, and Gibbs EL. Blood flow in brain and leg of man, and changes induced by alteration of blood gases. J Clin Invest 11: 1155-1177, 1932[Medline].

98.   Levine, BD, Giller CA, Lane LD, Buckey JC, and Blomqvist CG. Cerebral versus systemic hemodynamics during graded orthostatic stress in humans. Circulation 90: 298-306, 1994[Abstract/Free Full Text].

99.   Lipsitz, LA, Mukai S, Hamner J, Gagnon M, and Babikian V. Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension. Stroke 31: 1897-1903, 2000[Abstract/Free Full Text].

100.   Lodi, CA, Ter MA, Beydon L, and Ursino M. Modeling cerebral autoregulation and CO₂ reactivity in patients with severe head injury. Am J Physiol Heart Circ Physiol 274: H1729-H1741, 1998[Abstract/Free Full Text].

101.   Lopez-Muniz, R, Stephens NL, Bromberger-Barnea B, Permutt S, and Riley RL. Critical closure of pulmonary vessels analyzed in terms of Starling resistor model. J Appl Physiol 24: 625-635, 1968[Free Full Text].

102.   Low, PA, Novak V, Spies JM, Novak P, and Petty GW. Cerebrovascular regulation in the postural orthostatic tachycardia syndrome (POTS). Am J Med Sci 317: 124-133, 1999[Web of Science][Medline].

103.   Lundvall, J, and Bjerkhoel P. Failure of hemoconcentration during standing to reveal plasma volume decline induced in the erect posture. J Appl Physiol 77: 2155-2162, 1994[Abstract/Free Full Text].

104.   Mack, GW, Yang R, Hargens AR, Nagashima K, and Haskell A. Influence of hydrostatic pressure gradients on regulation of plasma volume after exercise. J Appl Physiol 85: 667-675, 1998[Abstract/Free Full Text].

105.   MacKenzie, ET, Farrar JK, Fitch W, Graham DI, Gregory PC, and Harper AM. Effects of hemorrhagic hypotension on the cerebral circulation. I. Cerebral blood flow and pial arteriolar caliber. Stroke 10: 711-718, 1979[Free Full Text].

106.   Madsen, P, Lyck F, Pedersen M, Olesen HL, Nielsen H, and Secher NH. Brain and muscle oxygen saturation during head-up-tilt-induced central hypovolaemia in humans. Clin Physiol 15: 523-533, 1995[Web of Science][Medline].

107.   Madsen, P, Pott F, Olsen SB, Nielsen HB, Burcev I, and Secher NH. Near-infrared spectrophotometry determined brain oxygenation during fainting. Acta Physiol Scand 162: 501-507, 1998[Web of Science][Medline].

108.   Madsen, P, Svendsen LB, Jorgensen LG, Matzen S, Jansen E, and Secher NH. Tolerance to head-up tilt and suspension with elevated legs. Aviat Space Environ Med 69: 781-784, 1998[Medline].

109.   Madsen, PL, and Secher NH. Near-infrared oximetry of the brain. Prog Neurobiol 58: 541-560, 1999[Web of Science][Medline].

110.   Marmarou, A, Shulman K, and LaMorgese J. Compartmental analysis of compliance and outflow resistance of the cerebrospinal fluid system. J Neurosurg 43: 523-534, 1975[Web of Science][Medline].

111.   Mattle, HP, Nirkko AC, Baumgartner RW, and Sturzenegger M. Transient cerebral circulatory arrest coincides with fainting in cough syncope. Neurology 45: 498-501, 1995[Abstract/Free Full Text].

112.   Mehagnoul-Schipper, DJ, Vloet LC, Colier WNJM, Hoefnagels WHL, and Jansen RWMM Cerebral oxygenation declines in healthy elderly subjects in response to assuming the upright position. Stroke 31: 1615-1620, 2000[Abstract/Free Full Text].

113.   Moskowitz, MA, and Macfarlane R. Autonomic and neurohumoral control of the cerebral circulation. In: Autonomic Failure. A Textbook of Clinical Disorders of The Autonomic Nervous System, edited by Mathias CJ, and Bannister R.. Oxford, UK: Oxford Univ. Press, 1999, p. 76-81.

114.   Murkin, JM, Farrar JK, Tweed WA, McKenzie FN, and Guiraudon G. Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass: the influence of Pa_CO2. Anesth Analg 66: 825-832, 1987[Abstract/Free Full Text].

115.   Nagi, MM, and Ward ME. Modulation of myogenic responsiveness by CO₂ in rat diaphragmatic arterioles: role of the endothelium. Am J Physiol Heart Circ Physiol 272: H1419-H1425, 1997[Abstract/Free Full Text].

116.   Newell, DW, Aaslid R, Lam A, Mayberg TS, and Winn HR. Comparison of flow and velocity during dynamic autoregulation testing in humans. Stroke 25: 793-797, 1994[Abstract].

117.   Njemanze, PC. Critical limits of pressure-flow relation in the human brain. Stroke 23: 1743-1747, 1992[Abstract/Free Full Text].

118.   Novak, V, Spies JM, Novak P, McPhee BR, Rummans TA, and Low PA. Hypocapnia and cerebral hypoperfusion in orthostatic intolerance. Stroke 29: 1876-1881, 1998[Abstract/Free Full Text].

119.   Olsen, KS, Svendsen LB, and Larsen FS. Validation of transcranial near-infrared spectroscopy for evaluation of cerebral blood flow autoregulation. J Neurosurg Anesthesiol 8: 280-285, 1996[Web of Science][Medline].

120.   Olufsen, MS, Nadim A, and Lipsitz LA. Dynamics of cerebral blood flow regulation explained using a lumped parameter model. Am J Physiol Regul Integr Comp Physiol 282: R611-R622, 2002[Abstract/Free Full Text].

121.   Onrot, J, Bernard GR, Biaggioni I, Hollister AS, and Robertson D. Direct vasodilator effect of hyperventilation-induced hypocarbia in autonomic failure patients. Am J Med Sci 301: 305-309, 1991[Web of Science][Medline].

122.   Panerai, RB. Assessment of cerebral pressure autoregulation in humansa review of measurement methods. Physiol Meas 19: 305-338, 1998[Web of Science][Medline].

123.   Panerai, RB, Dawson SL, and Potter JF. Linear and nonlinear analysis of human dynamic cerebral autoregulation. Am J Physiol Heart Circ Physiol 277: H1089-H1099, 1999[Abstract/Free Full Text].

124.   Panerai, RB, Deverson ST, Mahony P, Hayes P, and Evans DH. Effects of CO₂ on dynamic cerebral autoregulation measurement. Physiol Meas 20: 265-275, 1999[Web of Science][Medline].

125.   Panerai, RB, Rennie JM, Kelsall AW, and Evans DH. Frequency-domain analysis of cerebral autoregulation from spontaneous fluctuations in arterial blood pressure. Med Biol Eng Comput 36: 315-322, 1998[Web of Science][Medline].

126.   Paulson, OB, Strandgaard S, and Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 2: 161-192, 1990[Web of Science][Medline].

127.   Pawelczyk, JA, Hanel B, Pawelczyk RA, Warberg J, and Secher NH. Leg vasoconstriction during dynamic exercise with reduced cardiac output. J Appl Physiol 73: 1838-1846, 1992[Abstract/Free Full Text].

128.   Perko, G, Payne G, and Secher NH. An indifference point for electrical impedance in humans. Acta Physiol Scand 148: 125-129, 1993[Web of Science][Medline].

129.   Piorry, PA. Recherches sur l'influence de la pesanteur sur le cours du sang; diagnostic de la syncope et de l'apoplexie; cause et traitement de la syncope. Arch Gén Médecine 12: 527-544, 1826.

130.   Pott, F, Van Lieshout JJ, Ide K, Madsen P, and Secher NH. Middle cerebral artery blood velocity during a Valsalva maneuver in the standing position. J Appl Physiol 88: 1545-1550, 2000[Abstract/Free Full Text].

131.  Pott F, Van Lieshout JJ, Ide K, Madsen P, and Secher NH. Middle cerebral artery blood velocity during intensive exercise is dominated by a Valsalva maneuver. J Appl Physiol published November 15, 2002, 10.1152/japplphysiol.00457. 2002.

132.   Poulin, MJ, Liang PJ, and Robbins PA. Dynamics of the cerebral blood flow response to step changes in end-tidal PCO₂ and PO₂ in humans. J Appl Physiol 81: 1084-1095, 1996[Abstract/Free Full Text].

133.   Remmen, JJ, Aengevaeren WR, Verheugt FW, Van ver Werf T, Luijten HE, Bos A, and Jansen RW. Finapres arterial pulse wave analysis with Modelflow is not a reliable non-invasive method for assessment of cardiac output. Clin Sci (Lond) 103: 143-149, 2002[Medline].

134.   Richards, HK, Czosnyka M, and Pickard JD. Assessment of critical closing pressure in the cerebral circulation as a measure of cerebrovascular tone. Acta Neurochir (Wien) 141: 1221-1227, 1999[Medline].

135.   Richardson, DW, Kontos HA, Raper AJ, and Patterson JLJ Systemic circulatory responses to hypocapnia in man. Am J Physiol 223: 1308-1312, 1972[Free Full Text].

136.   Roddie, IC. Human responses to emotional stress. Ir J Med Sci 146: 395-417, 1977[Web of Science][Medline].

137.   Rosner, MJ, and Coley IB. Cerebral perfusion pressure, intracranial pressure, and head elevation. J Neurosurg 65: 636-641, 1986[Web of Science][Medline].

138.   Rowell, LB. Control of regional blood flow during dynamic exercise. In: Human Cardiovascular Control, edited by Rowell LB.. New York: Oxford Univ. Press, 1993, p. 204-254.

139.   Rowell, LB. Passive effects of gravity. In: Human Cardiovascular Control, edited by Rowell LB.. New York: Oxford Univ. Press, 1993, p. 3-36.

140.   Sander-Jensen, K, Mehlsen J, Stadeager C, Christensen NJ, Fahrenkrug J, Schwartz TW, Warber J, and Bie P. Increase in vagal activity during hypotensive lower-body negative pressure in humans. Am J Physiol Regul Integr Comp Physiol 255: R149-R156, 1988[Abstract/Free Full Text].

141.   Sander-Jensen, K, Secher NH, Astrup A, Christensen NJ, Giese J, Schwartz TW, Warberg J, and Bie P. Hypotension induced by passive head-up tilt: endocrine and circulatory mechanisms. Am J Physiol Regul Integr Comp Physiol 251: R742-R748, 1986[Abstract/Free Full Text].

142.   Sato, J, Tachibana M, Numata T, Nishino T, and Konno A. Differences in the dynamic cerebrovascular response between stepwise up tilt and down tilt in humans. Am J Physiol Heart Circ Physiol 281: H774-H783, 2001[Abstract/Free Full Text].

143.   Sándor, P. Nervous control of the cerebrovascular system: doubts and facts. Neurochem Int 35: 237-259, 1999[Web of Science][Medline].

144.   Scheinberg, P, and Stead EA. The cerebral blood flow in male subjects as measured by the nitrous oxide technique. Normal values for blood flow, oxygen utilization, glucose utilization and peripheral resistance, with observations on the effect of tilting and anxiety. J Clin Invest 28: 1163-1171, 1949[Web of Science][Medline].

145.   Schmidt, W, Maassen N, Trost F, and Boning D. Training induced effects on blood volume, erythrocyte turnover and haemoglobin oxygen binding properties. Eur J Appl Physiol 57: 490-498, 1988[Web of Science].

146.   Schondorf, R, Benoit J, and Stein R. Cerebral autoregulation in orthostatic intolerance. Ann NY Acad Sci 940: 514-526, 2001[Web of Science][Medline].

147.   Schondorf, R, Benoit J, and Wein T. Cerebrovascular and cardiovascular measurements during neurally mediated syncope induced by head-up tilt. Stroke 28: 1564-1568, 1997[Abstract/Free Full Text].

148.   Schondorf, R, Stein R, Roberts R, Benoit J, and Cupples W. Dynamic cerebral autoregulation is preserved in neurally mediated syncope. J Appl Physiol 91: 2493-2502, 2001[Abstract/Free Full Text].

149.   Schwartz, TW. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 85: 1411-1425, 1983[Web of Science][Medline].

150.   Serrador, JM, Picot PA, Rutt BK, Shoemaker JK, and Bondar RL. MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke 31: 1672-1678, 2000[Abstract/Free Full Text].

151.   Shannon, JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, and Robertson D. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 342: 541-549, 2000[Abstract/Free Full Text].

152.   Shapiro, W, Wasserman AJ, Baker JP, and Patterson JL. Cerebrovascular response to acute hypocapnic and eucapnic hypoxia in normal man. J Clin Invest 49: 2362-2368, 1970[Web of Science][Medline].

153.   Sharpey-Schafer, EP. The mechanism of syncope after coughing. Br Med J ii: 860-863, 1953.

154.   Sharpey-Schafer, EP. Emergencies in general practice. Syncope. Br Med J i: 506-509, 1956.

155.   Smit, AAJ, Halliwill JR, Low PA, and Wieling W. Pathophysiological basis of orthostatic hypotension in autonomic failure. Topical review. J Physiol 519: 1-10, 1999[Abstract/Free Full Text].

156.   Smith, ML, Hudson DL, and Raven PB. Effect of muscle tension on the cardiovascular responses to lower body negative pressure in man. Med Sci Sports Exerc 19: 436-442, 1987.

157.   Sprangers, RLH, Wesseling KH, Imholz ALT, Imholz BPM, and Wieling W. Initial blood pressure fall on stand up and exercise explained by changes in total peripheral resistance. J Appl Physiol 70: 523-530, 1991[Abstract/Free Full Text].

158.   Stewart, JM, and Weldon A. Reflex vascular defects in the orthostatic tachycardia syndrome of adolescents. J Appl Physiol 90: 2025-2032, 2001[Abstract/Free Full Text].

159.   Sutton, R. Vasovagal syncopecould it be malignant? Eur J Card Pacing Electrophysiol 2: 89, 1992.

160.   Sutton, R. Vasovagal syncope: prevalence and presentation. An algorithm of management in the aviation environment. Eur Heart J, Suppl 1: D109-D113, 1999[Web of Science][Medline].

161.   Ten Harkel, ADJ, Van Lieshout JJ, Karemaker JM, and Wieling W. Differences in circulatory control in normal subjects who faint and who do not faint during orthostatic stress. Clin Auton Res 3: 117-124, 1993[Medline].

162.   Ten Harkel, ADJ, Van Lieshout JJ, and Wieling W. Effects of leg muscle pumping and tensing on orthostatic arterial pressure: a study in normal subjects and patients with autonomic failure. Clin Sci (Lond) 87: 553-558, 1994[Medline].

163.   Thomas, DJ, and Bannister R. Preservation of autoregulation of cerebral blood flow in autonomic failure. J Neurol Sci 44: 205-212, 1980[Web of Science][Medline].

164.   Tiecks, FP, Lam AM, Aaslid R, and Newell DW. Comparison of static and dynamic cerebral autoregulation measurements. Stroke 26: 1014-1019, 1995[Abstract/Free Full Text].

165.   Tiecks, FP, Lam AM, Matta BF, Strebel S, Douville C, and Newell DW. Effects of the Valsalva maneuver on cerebral circulation in healthy adults. A transcranial Doppler study. Stroke 26: 1386-1392, 1995[Abstract/Free Full Text].

166.   Toska, K, and Eriksen M. Respiration-synchronous fluctuations in stroke volume, heart rate and arterial pressure in humans. J Physiol 472: 501-512, 1993[Web of Science][Medline].

167.   Toung, TJK, Aizawa H, and Traystman RJ. Effects of positive end-expiratory pressure ventilation on cerebral venous pressure with head elevation in dogs. J Appl Physiol 88: 655-661, 2000[Abstract/Free Full Text].

168.   Umeyama, T, Kugimiya T, Ogawa T, Kandori Y, Ishizuka A, and Hanaoka K. Changes in cerebral blood flow estimated after stellate ganglion block by single photon emission computed tomography. J Auton Nerv Syst 50: 339-346, 1995[Web of Science][Medline].

169.   Ursino, M, and Lodi CA. A simple mathematical model of the interaction between intracranial pressure and cerebral hemodynamics. J Appl Physiol 82: 1256-1269, 1997[Abstract/Free Full Text].

170.   Ursino, M, and Lodi CA. Interaction among autoregulation, CO₂ reactivity, and intracranial pressure: a mathematical model. Am J Physiol Heart Circ Physiol 274: H1715-H1728, 1998[Abstract/Free Full Text].

171.   Van der Zee, JS, Arridge SR, Cope M, and Delpy DT. The effect of optode positioning on optical pathlength in near infrared spectroscopy of brain. Adv Exp Med Biol 277: 79-84, 1990[Medline].

172.  Van Lieshout JJ and Karemaker JM. Tracking of cardiac output from arterial pulse wave (Letter). Clin Sci (Lond) In Press.

173.   Van Lieshout, JJ, Pott F, Madsen PL, Van Goudoever J, and Secher NH. Muscle tensing during standing: effects on cerebral tissue oxygenation and cerebral artery blood velocity. Stroke 32: 1546-1551, 2001[Abstract/Free Full Text].

174.   Van Lieshout, JJ, Ten Harkel ADJ, and Wieling W. Physical manoeuvres for combating orthostatic dizziness in autonomic failure. Lancet 339: 897-898, 1992[Web of Science][Medline].

175.   Van Lieshout, JJ, Wieling W, and Karemaker JM. Neural circulatory control in vasovagal syncope. Pacing Clin Electrophysiol 20: 753-763, 1997[Medline].

176.   Van Lieshout, JJ, Wieling W, Karemaker JM, and Eckberg DL. The vasovagal response. Clin Sci (Lond) 81: 575-586, 1991[Medline].

177.   Van Mil, AHM, Spilt A, Van Buchem MA, Bollen ELEM, Thomsen G, Westendorp RGJ, and Blauw GJ. Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans. J Appl Physiol 92: 962-966, 2002[Abstract/Free Full Text].

178.   Visocchi, M, Chiappini F, Cioni B, and Meglio M. Cerebral blood flow velocities and trigeminal ganglion stimulation. A transcranial Doppler study. Stereotact Funct Neurosurg 66: 184-192, 1996[Web of Science][Medline].

179.   Weissler, AMW, and Warren JV. Vasodepressor syncope. Am Heart J 40: 786-794, 1959.

180.   Wesseling, KH, Jansen JRC, Settels JJ, and Schreuder JJ. Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 74: 2566-2573, 1993[Abstract/Free Full Text].

181.   Weyland, A, Buhre W, Grund S, Ludwig H, Kazmaier S, Weyland W, and Sonntag H. Cerebrovascular tone rather than intracranial pressure determines the effective downstream pressure of the cerebral circulation in the absence of intracranial hypertension. J Neurosurg Anesthesiol 12: 210-216, 2000[Web of Science][Medline].

182.   Weyland, A, Stephan H, Kazmaier S, Weyland W, Schorn B, Grune F, and Sonntag H. Flow velocity measurements as an index of cerebral blood flow. Validity of transcranial Doppler sonographic monitoring during cardiac surgery. Anesthesiology 81: 1401-1410, 1994[Web of Science][Medline].

183.   Whinnery, JE, and Shender BS. The opticogravic nerve: eye-level anatomic relationships within the central nervous system. Aviat Space Environ Med 64: 952-954, 1993[Medline].

184.   Wieling, W, Harms MPM, Ten Harkel ADJ, Van Lieshout JJ, and Sprangers RLH Circulatory response evoked by a 3 s bout of dynamic leg exercise in humans. J Physiol 494: 601-611, 1996[Abstract/Free Full Text].

185.   Wieling, W, and Van Lieshout JJ. The fainting lark. Clin Auton Res 12: 207, 2002[Web of Science][Medline].

186.   Wieling, W, Van Lieshout JJ, and Ten Harkel ADJ Dynamics of circulatory adjustments to head-up tilt and tilt-back in healthy and sympathetically denervated subjects. Clin Sci (Lond) 94: 347-352, 1998[Medline].

187.   Williams, IM, Picton A, Farrell A, Mead GE, Mortimer AJ, and McCollum CN. Light-reflective cerebral oximetry and jugular bulb venous oxygen saturation during carotid endarterectomy. Br J Surg 81: 1291-1295, 1994[Web of Science][Medline].

188.   Yilmaz, U, Cetinguc M, and Akin A. Visual symptoms and G-LOC in the operational environment and during centrifuge training of Turkish jet pilots. Aviat Space Environ Med 70: 709-712, 1999[Medline].

189.   Zhang, R, Zuckerman JH, Giller CA, and Levine BD. Transfer function analysis of dynamic cerebral autoregulation in humans. Am J Physiol Heart Circ Physiol 274: H233-H241, 1998[Abstract/Free Full Text].

190.   Zhang, R, Zuckerman JH, and Levine BD. Deterioration of cerebral autoregulation during orthostatic stress. J Appl Physiol 85: 1113-1122, 1998[Abstract/Free Full Text].